EditorialPublication Exclusive

New data on late treatment effects should change physician–patient discussions

Just over a year ago, my editorial for HemOnc Today focused on times when strongly held opinions can get in the way of an objective assessment of data and pose challenges for deciding on the best care of our patients.

I used the issue of radiation therapy for early-stage Hodgkin’s lymphoma (HL) as the example.

Although I told myself in my first days with the HemOnc Today team that I would try very hard not to return to a subject, events of the past week have drawn me back to this.

John Sweetenham, MD
John Sweetenham

It started with a phone call from a friend. He was diagnosed with early-stage HL in 2001 and was treated with the standard of care at the time — four cycles of ABVD followed by involved-field radiation therapy (IFRT) to the mediastinum and neck. He had a great response and has been very well since then.

He called to let me know he has just been diagnosed with early-stage prostate cancer, for which he has decided to have surgery. The main purpose of his call was to ask whether I was aware of any association between HL and its treatment and prostate cancer — a surprising question in one respect, because he has followed the literature on late effects of HL therapy very closely and probably knows it better than I! I told him I do not think there is an association, and this led to a more general conversation about late effects.

Late effects

Several new and highly relevant studies have been published or presented in the last few months.

A report from the Netherlands looked at second cancer risk for up to 40 years in HL survivors treated between 1965 and 2000. Overall, the standardized incidence ratio was 4.6 compared with the general population, and the risk was still high 35 years after treatment.

As expected, the most common cancers were breast, lung and gastrointestinal, but the incidence of breast cancer was not lower in patients treated in the 1989-2000 study period. This is remarkable because this was the period in which reduced radiation fields and lower doses were introduced.

The same Dutch group also published results of a study that looked at risks for coronary heart disease in HL survivors. In this case, the patients were treated between 1965 and 1995, and the investigators studied the relationship between radiation dose and subsequent development of coronary heart disease.

They reported a median interval from HL therapy to heart disease of 19 years and a linear relationship between the dose to the heart and the risk for coronary disease. Any additional risk factor for coronary disease, such as hypertension or hypercholesterolemia, independently increased the risk. The researchers conclude that the linear dose–response relationship can be used to predict the risk for heart disease and will help in the prevention or early management of this disease.

The editorial that accompanies this study identifies three possible strategies for minimizing cardiovascular risk based on the results. They are reducing the radiation dose, shrinking the treated volume, and using 3-D techniques for planning to increase the accuracy of therapy and reduce collateral damage.

The evidence base for each of these approaches is strong and rationally described. Remarkably, the editorial does not present balanced data for a fourth potential strategy — dropping radiation from the treatment. This is a pretty significant omission in view of the fact we now have data from prospective randomized trials that suggest this is a reasonable strategy when used alongside functional imaging.

Role of radiation

The first such study is the RAPID trial. This United Kingdom-based trial included 602 patients with low-risk, limited-stage HL who were treated with ABVD for three cycles, after which they underwent CT/PET scans. The 145 patients (24%) who were PET positive received the standard of care with one further cycle of ABVD followed by IFRT. PET-negative patients were randomly assigned IFRT or no further therapy (chemotherapy only).

The study, powered as a noninferiority trial, concluded that PFS was not noninferior in the chemotherapy-only arm. At first glance, this might seem to support the use of IFRT for all patients, but the PFS and OS curves tell a very different story. Although it is true there is some “daylight” between the PFS curves in favor of the IFRT arm, the fact is most patients on the chemotherapy-only arm had remarkably favorable outcomes, with 5-year PFS in excess of 80%.

At the ASH Annual Meeting and Exposition in December, David J. Straus, MD, presented early data from the CALGB 50604 trial. This was a phase 2 trial of patients with favorable-risk early-stage HL who received two cycles of ABVD followed by an interim CT/PET. PET-positive patients (9%) received an escalated chemotherapy regimen plus IFRT. PET-negative patients received two additional cycles of ABVD and no IFRT. The estimated 3-year PFS for PET-negative patients was 93%.

There are some important differences between the two trials, notably that the criteria for PET negativity differed — this explains why the rate of PET negativity in the CALGB trial was higher, suggesting that slightly more relaxed criteria for PET negativity can be used without compromising the outcome for PET-negative patients. This approach has yet to be tested in a randomized trial.

Taken together, the results of these studies suggest most patients with low-risk, early-stage HL can be effectively treated without radiation therapy, using CT/PET as an early biomarker of response. Functional imaging goes one step along the way of identifying those patients who can be spared the potential late toxicity of IFRT and, unless one believes that radiation therapy has other collateral benefits rather than late toxicities, this has to be the preferred approach.

There are encouraging data to suggest that many oncologists are “voting with their feet” over the IFRT issue.

A study using the National Cancer Data Base has shown that, in patients with stage I disease, the use of radiation has dropped from 53% in 2000 to 40% in 2012. Radiation use for stage II disease declined from 52% to 36% during that period. This trend has most likely been stimulated by the known late effects of radiation and facilitated by the incorporation of a chemotherapy-only approach into the National Comprehensive Cancer Network (NCCN) guidelines; although, the divergence of approach based on Deauville score as outlined by NCCN is not fully supported by available trial data.

Overall, emerging data suggest that a chemotherapy-only approach is reasonable for patients with low-risk, early-stage HL with a negative interim PET. It is likely that the inclusion of IFRT in this group does have a small PFS benefit (and at least one retrospective study suggests an OS benefit), but this needs to be weighed against the potential for late toxicity.

Of course, it is very difficult to consider dropping a potentially curative treatment modality. I have heartburn when I hear investigators talk about the potential for “chemotherapy-free” treatment of HL now that newer targeted agents are available. It would certainly be helpful if we had more reliable biomarkers than PET, and many of these are under investigation.

For now, we have enough data to present our patients with this information and allow them to participate in the treatment decision rather than recommending IFRT to everyone. My friend was presented with options for the management of his newly diagnosed prostate cancer, considered the relative pros and cons of each of these approaches, and made an informed decision that is right for him.

We should be giving our patients with early-stage HL the same opportunity to be participants in their treatment decisions.

References:

Goyal G, et al. Clin Lymphoma Myeloma Leuk. 2016;doi:10.1016/j.clml.2015.11.006.

Maraldo MV and Ng AK. J Clin Oncol. 2015;doi:10.1200/JCO.2015.64.6588.

Radford J, et al. New Engl J Med. 2015;doi:10.1056/NEJMe1511947.

Schaapveld M, et al. New Engl J Med. 2015;doi:10.1056/NEJMoa1505949.

Straus DJ, et al. Abstract 587. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

van Nimwegen FA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.63.4444.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.

Just over a year ago, my editorial for HemOnc Today focused on times when strongly held opinions can get in the way of an objective assessment of data and pose challenges for deciding on the best care of our patients.

I used the issue of radiation therapy for early-stage Hodgkin’s lymphoma (HL) as the example.

Although I told myself in my first days with the HemOnc Today team that I would try very hard not to return to a subject, events of the past week have drawn me back to this.

John Sweetenham, MD
John Sweetenham

It started with a phone call from a friend. He was diagnosed with early-stage HL in 2001 and was treated with the standard of care at the time — four cycles of ABVD followed by involved-field radiation therapy (IFRT) to the mediastinum and neck. He had a great response and has been very well since then.

He called to let me know he has just been diagnosed with early-stage prostate cancer, for which he has decided to have surgery. The main purpose of his call was to ask whether I was aware of any association between HL and its treatment and prostate cancer — a surprising question in one respect, because he has followed the literature on late effects of HL therapy very closely and probably knows it better than I! I told him I do not think there is an association, and this led to a more general conversation about late effects.

Late effects

Several new and highly relevant studies have been published or presented in the last few months.

A report from the Netherlands looked at second cancer risk for up to 40 years in HL survivors treated between 1965 and 2000. Overall, the standardized incidence ratio was 4.6 compared with the general population, and the risk was still high 35 years after treatment.

As expected, the most common cancers were breast, lung and gastrointestinal, but the incidence of breast cancer was not lower in patients treated in the 1989-2000 study period. This is remarkable because this was the period in which reduced radiation fields and lower doses were introduced.

The same Dutch group also published results of a study that looked at risks for coronary heart disease in HL survivors. In this case, the patients were treated between 1965 and 1995, and the investigators studied the relationship between radiation dose and subsequent development of coronary heart disease.

They reported a median interval from HL therapy to heart disease of 19 years and a linear relationship between the dose to the heart and the risk for coronary disease. Any additional risk factor for coronary disease, such as hypertension or hypercholesterolemia, independently increased the risk. The researchers conclude that the linear dose–response relationship can be used to predict the risk for heart disease and will help in the prevention or early management of this disease.

The editorial that accompanies this study identifies three possible strategies for minimizing cardiovascular risk based on the results. They are reducing the radiation dose, shrinking the treated volume, and using 3-D techniques for planning to increase the accuracy of therapy and reduce collateral damage.

The evidence base for each of these approaches is strong and rationally described. Remarkably, the editorial does not present balanced data for a fourth potential strategy — dropping radiation from the treatment. This is a pretty significant omission in view of the fact we now have data from prospective randomized trials that suggest this is a reasonable strategy when used alongside functional imaging.

Role of radiation

The first such study is the RAPID trial. This United Kingdom-based trial included 602 patients with low-risk, limited-stage HL who were treated with ABVD for three cycles, after which they underwent CT/PET scans. The 145 patients (24%) who were PET positive received the standard of care with one further cycle of ABVD followed by IFRT. PET-negative patients were randomly assigned IFRT or no further therapy (chemotherapy only).

PAGE BREAK

The study, powered as a noninferiority trial, concluded that PFS was not noninferior in the chemotherapy-only arm. At first glance, this might seem to support the use of IFRT for all patients, but the PFS and OS curves tell a very different story. Although it is true there is some “daylight” between the PFS curves in favor of the IFRT arm, the fact is most patients on the chemotherapy-only arm had remarkably favorable outcomes, with 5-year PFS in excess of 80%.

At the ASH Annual Meeting and Exposition in December, David J. Straus, MD, presented early data from the CALGB 50604 trial. This was a phase 2 trial of patients with favorable-risk early-stage HL who received two cycles of ABVD followed by an interim CT/PET. PET-positive patients (9%) received an escalated chemotherapy regimen plus IFRT. PET-negative patients received two additional cycles of ABVD and no IFRT. The estimated 3-year PFS for PET-negative patients was 93%.

There are some important differences between the two trials, notably that the criteria for PET negativity differed — this explains why the rate of PET negativity in the CALGB trial was higher, suggesting that slightly more relaxed criteria for PET negativity can be used without compromising the outcome for PET-negative patients. This approach has yet to be tested in a randomized trial.

Taken together, the results of these studies suggest most patients with low-risk, early-stage HL can be effectively treated without radiation therapy, using CT/PET as an early biomarker of response. Functional imaging goes one step along the way of identifying those patients who can be spared the potential late toxicity of IFRT and, unless one believes that radiation therapy has other collateral benefits rather than late toxicities, this has to be the preferred approach.

There are encouraging data to suggest that many oncologists are “voting with their feet” over the IFRT issue.

A study using the National Cancer Data Base has shown that, in patients with stage I disease, the use of radiation has dropped from 53% in 2000 to 40% in 2012. Radiation use for stage II disease declined from 52% to 36% during that period. This trend has most likely been stimulated by the known late effects of radiation and facilitated by the incorporation of a chemotherapy-only approach into the National Comprehensive Cancer Network (NCCN) guidelines; although, the divergence of approach based on Deauville score as outlined by NCCN is not fully supported by available trial data.

Overall, emerging data suggest that a chemotherapy-only approach is reasonable for patients with low-risk, early-stage HL with a negative interim PET. It is likely that the inclusion of IFRT in this group does have a small PFS benefit (and at least one retrospective study suggests an OS benefit), but this needs to be weighed against the potential for late toxicity.

Of course, it is very difficult to consider dropping a potentially curative treatment modality. I have heartburn when I hear investigators talk about the potential for “chemotherapy-free” treatment of HL now that newer targeted agents are available. It would certainly be helpful if we had more reliable biomarkers than PET, and many of these are under investigation.

For now, we have enough data to present our patients with this information and allow them to participate in the treatment decision rather than recommending IFRT to everyone. My friend was presented with options for the management of his newly diagnosed prostate cancer, considered the relative pros and cons of each of these approaches, and made an informed decision that is right for him.

We should be giving our patients with early-stage HL the same opportunity to be participants in their treatment decisions.

References:

Goyal G, et al. Clin Lymphoma Myeloma Leuk. 2016;doi:10.1016/j.clml.2015.11.006.

PAGE BREAK

Maraldo MV and Ng AK. J Clin Oncol. 2015;doi:10.1200/JCO.2015.64.6588.

Radford J, et al. New Engl J Med. 2015;doi:10.1056/NEJMe1511947.

Schaapveld M, et al. New Engl J Med. 2015;doi:10.1056/NEJMoa1505949.

Straus DJ, et al. Abstract 587. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

van Nimwegen FA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.63.4444.

For more information:

John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director at Huntsman Cancer Institute at the University of Utah. He can be reached at john.sweetenham@hci.utah.edu.

Disclosure: Sweetenham reports no relevant financial disclosures.